Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cooked meat mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) produces tumors at multiple sites in the F344 rat, including adenocarcinomas of the colon. In the present study, the development of IQ-induced colorectal tumors was shown to be accompanied by the progressive inhibition of programmed cell death. This was associated with increased expression of the antiapoptosis protein Bcl-2 and decreased expression of bax, a known activator of apoptosis. Carcinomas bearing high levels of bcl-2 expression exhibited low levels of p53, the tumor suppressor protein that in some circumstances has been shown to down-regulate bcl-2. Because they lack mutations in the genes commonly associated with increased cell proliferation (APC, Ki-ras, and p53) and show no evidence of microsatellite instability, IQ-induced colon tumors might arise via the deregulation of bcl-2 expression, leading to inhibition of programmed cell death.
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PMID:Inhibition of apoptosis in colon tumors induced in the rat by 2-amino-3-methylimidazo[4,5-f]quinoline. 881 12

p53 is a multifunctional tumor suppressor protein involved in the negative control of cell growth. Mutations in p53 cause alterations in cellular phenotype, including immortalization, neoplastic transformation, and resistance to DNA-damaging drugs. To help dissect distinct functions of p53, a set of genetic suppressor elements (GSEs) capable of inducing different p53-related phenotypes in rodent embryo fibroblasts was isolated from a retroviral library of random rat p53 cDNA fragments. All the GSEs were 100-300 nucleotides long and were in the sense orientation. They fell into four classes, corresponding to the transactivator (class I), DNA-binding (class II), and C-terminal (class III) domains of the protein and the 3'-untranslated region of the mRNA (class IV). GSEs in all four classes promoted immortalization of primary cells, but only members of classes I and III cooperated with activated ras to transform cells, and only members of class III conferred resistance to etoposide and strongly inhibited transcriptional transactivation by p53. These observations suggest that processes related to control of senescence, response to DNA damage, and transformation involve different functions of the p53 protein and furthermore indicate a regulatory role for the 3'-untranslated region of p53 mRNA.
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PMID:Use of genetic suppressor elements to dissect distinct biological effects of separate p53 domains. 881 96

Poly(ADP-ribosyl)ation of mutant and wild-type p53 was studied in transformed and nontransformed rat cell lines constitutively expressing the temperature-sensitive p53135val. It was found that in both cell types at 37.5 degrees C, where overexpressed p53 exhibits mutant conformation and cytoplasmic localization, a considerable part of the protein was poly(ADP-ribosyl)ated. Using densitometric scanning, the molecular mass of the modified protein was estimated as 64 kD. Immunofluorescence studies with affinity purified anti-poly(ADP-ribose) transferase (pADPRT) antibodies revealed that, contrary to predictions, the active enzyme was located in the cytoplasm, while in nuclei chromatin was depleted of pADPRT. A distinct intracellular localization and action of pADPRT was found in the cell lines cultivated at 32.5 degrees C, where p53 adopts wild-type form. Despite nuclear coexistence of both proteins no significant modification of p53 was found. Since the strikingly shared compartmentalization of p53 and pADPRT was indicative of possible complex formation between the two proteins, reciprocal immunoprecipitation and immunoblotting were performed with anti-p53 and anti-pADPRT antibodies. A poly(ADP-ribosyl)ated protein of 116 kD constantly precipitated at stringent conditions was identified as the automodified enzyme. It is concluded that mutant cytoplasmic p53 is tightly complexed to pADPRT and becomes modified. At 32.5 degrees C binding to DNA of p53 or its temperature-dependent conformational alteration might prevent an analogous modification of the tumor suppressor protein.
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PMID:ADP-ribosylation of p53 tumor suppressor protein: mutant but not wild-type p53 is modified. 883 78

The group C adenovirus E4orf6 protein has previously been shown to bind to the p53 cellular tumor suppressor protein and block its ability to activate transcription. Here we show that the E4orf6 protein blocks the induction of p53-mediated apoptosis when AT6 cells, which harbor a temperature-sensitive p53, are shifted to the permissive temperature. The E4orf6 protein does not, however, prevent the induction of apoptosis in p53-deficient H1299 cells by treatment with tumor necrosis factor alpha and cycloheximide. The E4orf6 protein also cooperates with the adenovirus E1A protein to transform primary baby rat kidney cells, and it cooperates with the adenovirus E1A plus E1B 19-kDa and E1B 55-kDa proteins to increase the number of baby rat kidney cell transformants and enhance the rate at which they arise. The level of p53 is substantially reduced in transformed cells expressing the E4orf6 protein in comparison to adenovirus transformants lacking it. The E4orf6 gene also accelerates tumor formation when transformed baby rat kidney cells are injected subcutaneously into the nude mouse, and it converts human 293 cells from nontumorigenic to tumorigenic in nude mice. In addition to the well-studied E1A and E1B oncogenes, group C adenoviruses harbor a third oncogene, E4orf6, which functions in some respects similarly to the E1B oncogene.
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PMID:Oncogenic potential of the adenovirus E4orf6 protein. 887 29

Interleukin 2 (IL-2) and interleukin 4 (IL-4) secreted by activated but not by resting mature T cells are pleiotropic cytokines affecting growth and differentiation of diverse cell types, such as T cells, B cells, and mast cells. There is little information about the molecular basis for the constitutive repression of IL-2 and IL-4 gene expression in unstimulated T cells. We investigated the possibility that wild-type (wt) p53, a nuclear tumor suppressor protein, might serve to repress IL-2 and IL-4 gene expression in murine E14 T lymphoma and in human Jurkat cells. We transiently cotransfected these cells with constitutive simian virus 40 (SV 40) early promoter expression plasmids overproducing wt or mutant murine p53 and with appropriate luciferase (luc) reporter plasmids containing the promoter elements of murine IL-2 and IL-4 genes to evaluate the effect of various p53 species on these promoters. Murine wt p53 derived from pSG5p53cD strongly repressed the IL-2 and IL-4 promoters in both cell lines induced by the phorbol ester TPA and the Ca2+ ionophore ionomycin but not, however, in uninduced cells. In similar transient transfection experiments with lymphoma cells, overexpression of deletion mutant species of murine p53 revealed that the N-terminal and C-terminal domains are crucial for inhibition of both IL-2 and IL-4 gene expression. These parts of p53 comprise the transactivation domain at the amino terminal side, which has previously also been shown to interact with the TATA-box binding-protein TBP and the carboxy-terminal oligomerization domain. Additionally, it was shown that a previously described inhibitory protein, the high-mobility-group protein HMG-I/Y, does not functionally interact with p53. Cotransfection of expression plasmids for both p53 and HMG-I/Y did not alter the extent of inhibition by the individual proteins. These data suggest that p53 can downmodulate both IL-2 and IL-4 gene expression and that both the transactivation and oligomerization domains of the tumor suppressor protein are essential for this transcriptional repression.
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PMID:Repression of interleukin-2 and interleukin-4 promoters by tumor suppressor protein p53. 887 30

Serum antibodies reacting with the tumor suppressor protein p53 have been detected previously in cancer patients with a variety of neoplasms. Two initial (although insufficient) prerequisites for a B-cell response to occur have been proposed: p53 protein accumulation in the tumor or a mutant p53 gene, or both. We have examined 65 esophageal cancer cases (42 from Guangzhou and Shenyang, People's Republic of China, and 23 from Paris, France) to obtain a prevalence estimate of anti-p53 antibodies for this type of cancer and to define the relationship of p53 tumor status to B-cell immune response. Sera were analyzed in a triplicate assay (enzyme-linked immunoassay, immunoprecipitation, and immunoblot) for anti-p53 antibodies. Tumor DNA was screened for mutations in exons 5-8, and tumor tissue was examined by immunohistochemistry for abnormal p53 protein accumulation. p53 mutations were found in 36 (58%) of 62 cases analyzed. Sixteen patients (25%) had circulating antibodies to the tumor suppressor protein. All but two (88%) of the tumors from seropositive cases had a mutation in the DNA binding region of the p53 gene, and with one exception, these tumors also showed nuclear accumulation of the p53 protein. In contrast, tumor mutations were found in just 22 (46%) of the 48 individuals in whom we did not detect anti-p53 antibodies. Among the 22 seronegative cases for which we found no tumor mutations, 11 revealed p53 protein accumulation by immunohistochemical analysis. Thus, circulating anti-p53 antibodies may be present in one-fourth of esophageal cancer patients, most of whom also would be expected to have a p53 gene mutation in their tumors. Patients without such mutations appear considerably less likely to mount a B-cell response to the p53 tumor suppressor protein than those that do (P < 0.01).
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PMID:Circulating anti-p53 antibodies in esophageal cancer patients are found predominantly in individuals with p53 core domain mutations in their tumors. 889 44

The effect of the CSF-1 receptor, cFMS, on the phosphorylation of the retinoblastoma (RB) tumor suppressor protein and on the cell cycle and cell differentiation was analyzed in a cultured promyelocytic leukemia cell capable of induced myelomonocytic differentiation. A series of cFMS-transfected HL-60 sublines with progressively higher cell surface FMS expression was derived by flow cytometric cell sorting. Overexpression of FMS increased the duration of the cell cycle, prolonging all cell cycle phases especially S phase, which doubled. The increased cell cycle generation times occurred without any detectable changes in RB expression level or phosphorylation. For retinoic acid (RA)-induced myeloid differentiation, progressive overexpression of FMS caused a greater fraction of cells to differentiate and G1/0 arrest compared to wild-type cells after the same number of cell cycle generation times. FMS overexpression also progressively increased the relative amount of dephosphorylated RB protein induced, while reducing the total amount of RB protein. The inducer-originated and FMS-driven changes in RB hypophosphorylation were not effected through changes in p21/WAF1/CIP1 in this p53-negative cell. Similar effects on differentiation and G0 arrest occurred with 1,25-dihydroxy vitamin D3 (D3)-induced monocytic differentiation. FMS did not significantly affect myeloid differentiation induced by DMSO, which does not target steroid-thyroid hormone receptors like RA and D3. While differentiation is typically associated with hypophosphorylated RB in all these cases, the kinetics indicate that the FMS-induced changes in cell cycle and cell differentiation do not depend in a direct causal fashion on the interconversion between hyperphosphorylated and hypophosphorylated RB.
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PMID:FMS (CSF-1 receptor) prolongs cell cycle and promotes retinoic acid-induced hypophosphorylation of retinoblastoma protein, G1 arrest, and cell differentiation. 894 Feb 55

The Epstein-Barr virus (EBV) immediate early transactivator Zta is a basic leucine zipper (bZIP) transcription factor that causes G0/G1 cell cycle arrest through induction of the tumor suppressor protein, p53, and the cyclin-dependent kinase inhibitors, p21 and p27 (Cayrol, C., and Flemington, E. K. (1996) EMBO J. 15, 2748-2759). Here, we report a genetic analysis of Zta-mediated G0/G1 growth arrest and p21 induction. The majority of the Zta transactivation domain can be deleted (ZDelta1-128) without significantly affecting the ability of Zta to elicit growth arrest. A larger amino-terminal deletion (ZDelta1-167) abrogates the ability of Zta to inhibit proliferation, mapping the growth-inhibitory domain to a carboxyl-terminal region encompassing the bZIP domain (amino acids 128-245). The integrity of the bZIP domain is required for growth suppression since a two-amino acid mutant which is defective for homodimerization, fails to induce cell cycle arrest. Western blot analysis of p21 expression in cells expressing Zta mutants reveals that the ability of Zta mutants to cause G0/G1 growth arrest is intimately related to their capacity to induce p21 expression. Together, these data demonstrate that a carboxyl-terminal region of Zta that includes the bZIP domain is sufficient to mediate G0/G1 growth arrest and p21 induction.
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PMID:G0/G1 growth arrest mediated by a region encompassing the basic leucine zipper (bZIP) domain of the Epstein-Barr virus transactivator Zta. 894 19

Amplification of MDM2 and CDK4 is observed frequently in human sarcomas. Although overexpression of these protooncogenes might inhibit growth regulation through the TP53- and retinoblastoma tumor suppressor protein (RB)-mediated pathways, neither gene was included consistently in all of the amplicons observed in our sarcoma panel. It was unclear whether both of these genes were selected for during amplification. Furthermore, in some samples without amplification of MDM2 or CDK4, comparative genomic hybridization showed amplification in the 12q13-15 region, suggesting that another selection mechanism might also be involved. To investigate the possibility that another target gene, which may be located between CDK4 and MDM2, could be the driving force, we characterized the involvement of 17 loci from this region in 12q13-15 amplicons that were detected previously in 21 sarcoma samples. The results showed discrete amplicons around MDM2 and CDK4 with reduced amplification of the intervening sequences. This suggests that there is separate selection for amplification of the two genes, and it makes the possibility of a common selective gene unlikely. Furthermore, D12S8, localized distal to MDM2, was amplified almost as frequently as MDM2 and was also amplified in one of the samples without MDM2 or CDK4 amplification. The data suggest that amplification of at least three different regions within the 12q13-15 segment may be selected for in tumor cells involving MDM2, CDK4, or a more distally located gene, possibly near D12S8.
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PMID:Separate amplified regions encompassing CDK4 and MDM2 in human sarcomas. 894 7

The adenovirus type 5 (Ad5) early 1B (E1B) 55-kDa (E1B-55kDa)-E4orf6 protein complex has been implicated in the selective modulation of nucleocytoplasmic mRNA transport at late times after infection. Using a combined immunoprecipitation-immunoblotting assay, we mapped the domains in E1B-55kDa required for the interaction with the E4orf6 protein in lytically infected A549 cells. Several domains in the 496-residue 55-kDa polypeptide contributed to a stable association with the E4orf6 protein in E1B mutant virus-infected cells. Linker insertion mutations at amino acids 180 and 224 caused reduced binding of the E4orf6 protein, whereas linker insertion mutations at amino acid 143 and in the central domain of E1B-55kDa eliminated the binding of the E4orf6 protein. Earlier work showing that the central domain of E1B-55kDa is required for binding to p53 and the recent observation that the E4orf6 protein also interacts with the tumor suppressor protein led us to suspect that p53 might play a role in the E1B-E4 protein interaction. However, coimmunoprecipitation assays with extracts prepared from infected p53-negative H1299 cells established that p53 is not needed for the E1B-E4 protein interaction in adenovirus-infected cells. Using two different protein-protein interaction assays, we also mapped the region in the E4orf6 protein required for E1B-55kDa interaction to the amino-terminal 55 amino acid residues. Interestingly, both binding assays established that the same region in the E4orf6/7 protein can potentially interact with E1B-55kDa. Our results demonstrate that two distinct segments in the 55-kDa protein encoding the transformation and late lytic functions independently interact with p53 and the E4orf6 protein in vivo and provide further insight by which the multifunctional 55-kDa EIB protein can exert its multiple activities in lytically infected cells and in adenovirus transformation.
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PMID:Structural analysis of the adenovirus type 5 E1B 55-kilodalton-E4orf6 protein complex. 899 32


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